CMTDIG

Genetic Context

HGNC-Approved Gene Symbol

NEFL

Gene Full Name

neurofilament light chain

HGNC Gene Alias(es)

NFL, NF68

Chromosome

8p21.2

Zygosity of Responsible Variant

Heterozygous

Variant Mechanism

Dominant-Negative

Details

Confidence:
High

Prediction:
Functional and genetic evidence supports a dominant-negative mechanism for CMTDIG: neurofilaments are obligate copolymers nucleated by the light chain, and mutant NF-L from the dominant NEFL alleles co-assembles with normal subunits, blocks filament formation, and forms aggregates that stall axonal transport. Wild-type subunits supplied alongside are drawn into those aggregates rather than rescuing assembly. Biallelic NEFL null alleles instead cause the recessive subtype CMT2B5, a true loss of light chain.

Rationale:
Cooperative assembly is why one abnormal subunit costs more than a missing one: mutant NF-L is incorporated at the nucleation step and takes normal subunits with it, so a neuron loses far more filament than a halved gene dose would cost. Patients who make no light chain at all have the distinct recessive disease CMT2B5.

ClinVar Pathogenic Variants

View NEFL ClinVar Variants

CMTDIG OMIM Entry

CMTDIG OMIM

NEFL OMIM Entry

NEFL OMIM